U.S. patent application number 09/884466 was filed with the patent office on 2002-03-21 for cox-2 inhibitors and the prevention of the side effects of radiation therapy.
Invention is credited to Herbst, Arthur L., Weichselbaum, Ralph.
Application Number | 20020035139 09/884466 |
Document ID | / |
Family ID | 22792051 |
Filed Date | 2002-03-21 |
United States Patent
Application |
20020035139 |
Kind Code |
A1 |
Herbst, Arthur L. ; et
al. |
March 21, 2002 |
COX-2 inhibitors and the prevention of the side effects of
radiation therapy
Abstract
A generalized method is disclosed for reducing the deleterious
side effects of radiotherapy in subjects undergoing radiotherapy
for the treatment of cancer. The method is the administration to a
subject of a side-effect reducing amount of one or more selective
cyclooxygenase-2 (COX-2) inhibitor.
Inventors: |
Herbst, Arthur L.; (Chicago,
IL) ; Weichselbaum, Ralph; (Chicago, IL) |
Correspondence
Address: |
MCDERMOTT WILL & EMERY
600 13TH STREET, N.W.
WASHINGTON
DC
20005-3096
US
|
Family ID: |
22792051 |
Appl. No.: |
09/884466 |
Filed: |
June 20, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60212685 |
Jun 20, 2000 |
|
|
|
Current U.S.
Class: |
514/406 |
Current CPC
Class: |
A61K 31/00 20130101;
A61P 13/02 20180101; A61K 31/635 20130101; A61P 1/00 20180101; A61P
39/00 20180101; A61K 31/415 20130101; A61K 41/00 20130101; A61K
31/365 20130101; A61K 31/34 20130101; A61P 1/12 20180101; A61P
13/08 20180101 |
Class at
Publication: |
514/406 |
International
Class: |
A61K 031/415 |
Claims
We claim:
1. A method of reducing one or more deleterious side effect of
radiation treatment in a subject undergoing radiation treatment,
comprising administering to said subject a side-effect reducing
amount of a selective cyclooxygenase-2 inhibitor.
2. The method of claim 1, wherein the cyclooxygenase-2 inhibitor is
rofecoxib.
3. The method of claim 1, wherein the cyclooxygenase-2 inhibitor is
celecoxib.
4. The method of claim 1, wherein the reduced side effect comprises
an acute mucosal effect of radiation on the urinary or
gastrointestinal tract.
5. The method of claim 1, wherein the side effect reduced comprises
fatigue.
6. The method of claim 1, wherein the reduced side effect comprises
a disorder selected from the group consisting of diarrhea, rectal
bleeding, proctitis, and sigmoiditis.
7. The method of claim 1, wherein the reduced side effect comprises
urinary frequency, prostatitis, or cystitis.
8. The method of claim 1, wherein the radiation treatment is
directed outside the pelvis.
9. The method of claim 1, wherein the reduced side effect comprises
dermatitis.
Description
[0001] This application claims priority to U.S. provisional patent
application Serial No. 60/212,685, filed Jun. 20, 2000.
FIELD OF THE INVENTION
[0002] This invention is directed toward methods of reducing the
side effects associated with radiotherapy in cancer patients.
BACKGROUND OF THE INVENTION
[0003] The acute effects of radiotherapy are a result of the
interruption of rapidly dividing cell renewal systems. In the
pelvis, these effects may be manifested as acute radiation
proctitis, cystitis, prostatitis, as well as dermatitis. Presently,
the only FDA approved intervention for acute radiation effects is
the use of Ethiol, a sulfhydryl-containing compound (WR-2721), is
reported to decrease the dry mouth following radiation treatment
for head and neck cancer. However, Ethiol does not limit acute
mucosal effects and there is concern that Ethiol may actually
protect tumors. In addition, patients who receive even limited
field radiotherapy may develop fatigue, which may limit their
ability to tolerate treatment or to carry on daily activity.
[0004] Hallahan D E et al., Proc. Natl. Acad. Sci. USA 91(11):
4897-901 (1994) identified a signaling pathway involving the
activation of phospholipase A2 and protein kinase C in human cells
that confers x-ray induction of the tumor necrosis factor alpha
(TNF.alpha.) gene. Phospholipase A2 is involved in the production
of arachidonate, part of the prostaglandin synthesis pathway.
Recently, two isoforms of the enzymes that synthesize
prostaglandins have been identified. The first, COX-1, is a
constitutive enzyme that has a housekeeping physiological function.
The second, COX-2, is induced by diverse inflammatory stimuli,
oncoproteins and growth factors. COX-2 is known to promote
carcinogenesis as well as growth of established tumors and is
up-regulated in the high percentage of common human cancers. Thus,
COX-2 is a target for prevention as well as therapeutic
intervention.
SUMMARY OF THE INVENTION
[0005] The invention provides a method of reducing the side effects
associated with radiotherapy, comprising administering to a cancer
patient undergoing radiotherapy a cyclooxygenase-2 (COX-2)
inhibitor. COX-2 inhibitors inhibit the acute mucosal effects of
radiation, as well as associated fatigue, by blocking induction of
the COX-2 proteins.
[0006] The reduced side effects can include an acute mucosal effect
of radiation on the urinary or gastrointestinal tract; fatigue;
diarrhea, rectal bleeding, proctitis, or sigmoiditis; urinary
frequency, prostatitis, or cystitis; or dermatitis.
[0007] In one embodiment, the administered COX-2 inhibitor is
rofecoxib. In another embodiment, the administered COX-2 inhibitor
is celecoxib.
[0008] In one embodiment, the radiation treatment that causes the
side effects is directed outside of the pelvis. In another
embodiment, the radiation treatment that causes the side effects is
directed to the pelvic area.
DETAILED DESCRIPTION OF THE INVENTION
[0009] FIG. 1 is an interview form for determining fatigue
(FACT-An/fatigue Scoring Guidelines).
[0010] FIG. 2 is an interview form for determining fatigue
(FACIT-Fatigue Scale).
DETAILED DESCRIPTION OF THE INVENTION
[0011] The present invention originated with observations made
during pelvic radiation for prostate carcinoma. Our clinical
observations suggest that the use of COX-2 inhibitors,
Celebrex.RTM. (Celacoxib, Searle) and Vioxx.RTM. (Rofecoxib, Merck)
decrease the acute mucosal effects of radiation especially on the
urinary and gastrointestinal tracts, as well as associated fatigue
during radiotherapy.
[0012] COX-2 inhibitor agents given to patients receiving radiation
therapy to the pelvis can reduce the frequency of diarrhea and
rectal bleeding and the symptoms associated with proctitis and
sigmoiditis. Administration of these COX-2 inhibitor agents can
lessen urinary frequency and symptoms usually associated with
prostatitis in male and cystitis in individuals of both sexes.
Finally, administration of these COX-2 inhibitor agents during
radiation treatment can reduce the fatigue usually experienced by
patients receiving radiation and that this latter benefit will be
for patients receiving treatment to any site, including those
outside the pelvis.
[0013] COX-2 inhibitors decrease the acute side effects of
radiotherapy. These side effects are gastrointestinal and
hematological toxicity. These side effects include cystitis,
proctitis, prostatitis, pneumonitis and large and small bowel
irritation as reflected by diarrhea and other gastrointestinal
symptoms including nausea and vomiting. Additionally, mucosal
effects of radiotherapy including dermatitis, esophagitis, oral and
upper airway mucositis and the dermatitis seen in the intergenous
areas of the body including the breast/axillary fold, vulva/vaginal
folds and large skin fold areas in the abdomen can be protected
from the side effects of radiotherapy. The fatigue associated with
local and large field radiotherapy can be decreased by COX-2
inhibition.
[0014] In addition, COX-2 inhibitors have been shown to potentiate
the anti-tumor effects of radiotherapy, and unlike Ethiol, do not
carry the concern of radioprotection. COX-2 inhibitors can be given
to enhance patient well being and energy during and immediately
after radiotherapy treatment and may also be given to limit acute
effects of radiotherapy. Cox-2 inhibitors may replace
corticosteroids as treatment for some of the intermediate forms of
radiation pnuemonitis.
[0015] Background. Hallahan D E et al., "Membrane-derived second
messenger regulates x-ray-mediated tumor necrosis factor alpha gene
induction." Proc. Natl. Acad. Sci. USA 91(11): 4897-901 (1994)
identified a signaling pathway involving the activation of
phospholipase A2 and protein kinase C in human cells that confers
x-ray induction of the tumor necrosis factor alpha (TNF.alpha.)
gene. Treatment of human cells with ionizing radiation or
H.sub.2O.sub.2 was associated with the production of arachidonic
acid. Inhibition of phospholipase A2 abolished radiation-mediated
arachidonate production as well as, the subsequent activation of
protein kinase C and tumor necrosis factor alpha gene expression.
Hallahan showed that ionizing radiation-mediated gene expression in
human cells is regulated in part by extranuclear signal
transduction.
[0016] The arachadonic acid that is is produced is metabolized by
COX-2 to various metabolic products, which are chemoattractants for
inflammatory cells.
[0017] Subsequently, Steinauer K K et al., "Radiation induces up
regulation of Cox-2 protein in prostate cancer cells." Int. J. Rad.
Onc. Biol. Phys. 48(2): 325-8 (2000) investigated the impact of
gamma-irradiation on cyclooxygenase-2 (COX-2) expression and its
enzymatic activity in PC-3 cells. Cell cycle redistribution,
viability, and apoptosis were quantitated in control and irradiated
cells with or without the COX-2 inhibitor NS-398. Steinauer
observed a dose-dependent increase in COX-2 of following increased
irradiation dosages. The prostaglandin (PGE(2)) level in irradiated
cells was higher than in controls while cells irradiated in the
presence of NS-398 had reduced PGE(2) levels. Steinauer found no
differences in cell cycle distribution or apoptosis between cells
irradiated in the presence or absence of NS-398. Thus, COX-2
protein is up-regulated and enzymatically active after irradiation,
resulting in elevated levels of PGE(2). This effect can be
suppressed by NS-398, which has clinical implications for therapies
combining COX-2 inhibitors with radiation therapy.
[0018] The induction of proinflammatory cytokines TNF.alpha. and
IL-1 following exposure of cells and animals to ionizing radiation
have been reported. O'Brien-Ladner A et al., Radiat. Res. 136(1):
37-41 (1993). It is also known that cyclooxygenase inhibitors block
production of these cytokines. See also, Van Der Meeren A et al.
Radiat. Res. 155(6) 858-65 (2001).
[0019] Proposed Mechanism of Action; Tests. We propose that an
inflammatory response mediates in part the acute mucosal
intestinal, skin, lung, prostatic and bladder effects of ionizing
radiation. Additionally we propose that a component of radiation
induced fatigue is mediated by the inflammatory response and as
reflected by acute phase reactant proteins that increase during
radiotherapy.
[0020] We tested whether COX-2 inhibitors suppress TNF.alpha.
production following localized radiotherapy in mice. TNF.alpha.
production was not suppressed during times studied (24 hours
following radiation).
[0021] Thus, COX-2 inhibitors mediate their anti-radiation induced
inflammatory effects by directly inhibiting COX-2 and not
indirectly by inhibiting one class of cytokines. Accordingly, the
anti-inflammatory effects are not restricted to the effects of one
cytokine. Some of the long term effects of radiotherapy, fibrosis,
adhesions, and small volume necrosis can be inhibited or attenuated
by decreasing the inflammatory effects of radiation therapy.
[0022] Utility. The side effects of radiation for prostate cancer
include acute urinary side effects (see, Chou et al., Int. J.
Radiat. Oncol. Biol. Phys. 47:115 (2001); Dearnaly et al, Lancet
358: 267 (1999); O'Sullivan et al., Clin. Oncol. 12: 217 (2000)).
The acute urinary side effects can be at the GRI level (with
frequency of nocturia approx. 2.times. pretreatment, with a dysuria
urgency requiring no medication) or at the GRII level (with
frequency of nocturia less than hourly, with a dysuria urgency
requiring medication). In general, 30-40% of patients suffer at the
GRI level and 20-30% of patients suffer at the GRII level. Overall
50-60% of patients have these effects, which last approximately 6
months in duration. Some patients suffer the more severe GR III or
IV.
[0023] Many cancer patients are at risk for suffering the side
effects of radiation treatment. TABLE 1 below shows the cancer
incidence worldwide (Globocan, 2000), each of which can be treated
by radiation treatment.
1TABLE 1 CANCER INCIDENCE WORLDWIDE Cancer Type North America Cases
N. Europe Cases W. Europe Cases Breast 202,044 54,551 115,308
Cervix 14,845 6,049 13,282 Uterus 35,960 9,440 19,214 Prostate
211,950 37,046 84,856 Lung men 119,664 19,336 75,350 women 85,944
18,063 18,183 Colorectal men 83,777 26,409 61,128 women 80,896
24,953 58,255 Head & Neck men 13,731 3,746 17,026 women 8,914
1,980 5,119 TOTAL 857,725 201,573 467,721 TOTAL IN NORTH 1,527,019
AMERICA AND EUROPE
[0024] The method of the invention provides substantial benefit to
the patient population as a reduction in side-effects of 25% to 75%
is achieved. The sample size estimation for each group (treatment
and control) is provided in TABLE 2.
2TABLE 2 SAMPLE SIZE EXAMPLES Prevalence of side Prevalence of size
effects = effects = 60% 75% Expected reduction = 25% 60 --> 45%
75 --> 57% Alpha = 0.05 Power = 0.8 186 110 Power = 0.9 244 144
Alpha = 0.01 Power = 0.8 271 159 Power = 0.9 341 199 Expected
reduction = 50% 60 --> 30% 75 --> 37.5% Alpha = 0.05 Power =
0.8 49 32 Power = 0.9 63 40 Alpha = 0.01 Power = 0.8 70 45 Power =
0.9 86 55 Expected reduction = 75% 60 --> 15% 75 --> 19%
Alpha = 0.05 Power = 0.8 22 15 Power = 0.9 27 18 Alpha = 0.01 Power
= 0.8 30 21 Power = 0.9 37 25 Note: all the calculations are for
two-sided tests.
[0025] COX-2 Inhibitors. COX-2 inhibitors are known in the art and
disclosed, for example, in U.S. Pat. Nos. 6,245,797, 6,242,493,
6,235,764, 6,231,888, 6,222,048, 6,211,210, 6,211,189, 6,197,826,
6,136,831, 6,133,292, 6,071,954, 6,057,319, 6,046,217, 6,004,950,
5,994,379, 5,968,958, 5,925,631, 5,861,419, 5,817,700, 5,789,413,
5,733,909, 5,710,140, 5,698,584, 5,691,374, 5,639,780, 5,604,253,
5,550,142, 5,536,752, and 5,521,213, the contents of which are
incorporated herein by reference. Specific COX-2 inhibitors can
have many fewer side effects than other commonly used NSAIDS, which
inhibit both COX-1 and COX-2. A selective inhibitor of
cyclooxygenase-2 will have similar anti-inflammatory, antipyretic
and analgesic properties to a conventional non-steroidal
anti-inflammatory drug, and in addition would inhibit
hormone-induced uterine contractions and have potential anti-cancer
effects, but will have a diminished ability to induce some of the
mechanism-based side effects. In particular, such a compound should
have a reduced potential for gastrointestinal toxicity, a reduced
potential for renal side effects, a reduced effect on bleeding
times and possibly a lessened ability to induce asthma attacks in
aspirin-sensitive asthmatic subjects. U.S. Pat. No. 6,222,048. Two
particular COX-2 inhibitors are COX-2 inhibitors, Celebrex.RTM.
(Celacoxib, Searle) and Vioxx.RTM. (Rofecoxib, Merck).
[0026] COX-2 Inhibitor Administration. Administration of the COX-2
inhibitors are well known in art and disclosed, for example, in
U.S. Pat. Nos. 6,245,797, 6,242,493, 6,235,764, 6,231,888,
6,222,048, 6,211,210, 6,211,189, 6,197,826, 6,136,831, 6,133,292,
6,071,954, 6,057,319, 6,046,217, 6,004,950, 5,994,379, 5,968,958,
5,925,631, 5,861,419, 5,817,700, 5,789,413, 5,733,909, 5,710,140,
5,698,584, 5,691,374, 5,639,780, 5,604,253, 5,550,142, 5,536,752,
and 5,521,213, the contents of which are incorporated herein by
reference. For the treatment, the COX-2 inhibitors may be
administered orally, topically, parenterally, by inhalation spray
or rectally in dosage unit formulations containing conventional
non-toxic pharmaceutically acceptable carriers, adjuvants and
vehicles. The pharmaceutical compositions containing the COX-2
inhibitor may be in a form suitable for oral use, for example, as
tablets, troches, lozenges, aqueous or oily suspensions,
dispersible powders or granules, emulsions, hard or soft capsules,
or syrups or elixirs. Corapositions of COX-2 inhibitor intended for
oral use may be prepared according to any method known to the art
for the manufacture of pharmaceutical compositions and such
compositions may contain one or more agents selected from the group
consisting of sweetening agents, flavoring agents, coloring agents
and preserving agents in order to provide pharmaceutically elegant
and palatable preparations. Tablets contain the active ingredient
in admixture with nontoxic pharmaceutically acceptable excipients
that are suitable for the manufacture of tablets. Guidance for the
administration can be found in the U.S. Food and Drug approvals for
the administration of Celacoxib or Rofecoxib. The COX-2 inhibitors
are preferably administered at a dosage amount of about 0.01 to 200
mg/kg of body weight of the patient, preferably about 0.1 to 100
mg/kg of body weight per day.
[0027] Also, a method providing for the colonic delivery or
preferential metabolism of a COX-2 inhibitor is provided in U.S.
Pat. No. 6,231,888.
[0028] COX-2 Inhibitor Effectiveness. The effectiveness of the
method of the invention can be readily determined by an interview
and examination of the patient. A reduction in nocturia and dysuria
urgency (for example, an improvement in the patient from level GR
II to GRI, or from GR I to normal) is used as a determination that
the treatment is effective for the patient. More generally, an
analysis of the indices of patient improvement in groups of
patients using standardized test (see, FIG. 1 and FIG. 2) can be
used to determine that the method of the invention is effective
generally.
[0029] Also the effectiveness of the method of the invention can be
assayed using the reduction of acute phase response indicator
markers in the patients blood as compared with untreated patients
and control persons. Cengiz M et al., Int. J. Radiat. Oncol. Biol.
Phys. 49(4): 1093-6 (2001) has shown that acute phase response is
characterized by changes in the plasma concentrations of a number
of liver-synthesized proteins, one of which is C-reactive protein
(CRP). The existence of these changes in the plasma profile
underlies the change in erythrocyte sedimentation rate (ESR). CRP
level and ESR increase during radiotherapy and whether their rise
correlates with acute and late radiation morbidity. The increase
was more prominent in patients who were irradiated through
pelvic-paraaortic field than in patients with pelvic radiation.
Likewise, the indicator markers can be an increase of
RM3/1-positive macrophages, as shown by Handschel J et al., J.
Pathol. 193(2): 242-7 (2001) for radiation-induced oral
mucositis.
[0030] The effectiveness of the method of the invention can be
assayed by testing the prostate volume of (male) patients as
compared with untreated patients and control persons, using the
methods of analysis described by Speight J L et al., Int. J.
Radiat. Oncol. Biol. Phys. 48(5): 1461-7 (2000). Likewise, rectal
toxicity can be measured using the methods of Hovdenak N et al.,
Int. J. Radiat. Oncol. Biol. Phys. 48(4): 1111-7 (2000). Intestinal
inflammatory response can be tested using the methods of Freeman S
L et al., Int. J. Radiat. Biol. 77(3) 389-95 (2001).
[0031] Moreover, the method of the invention can be tested in
animal models, such as the rat model for radiation-induced
proctitis of Kang S et al, J. Korean Med. Sci. 15(6): 682-9
(2000).
[0032] The details of one or more embodiments of the invention are
set forth in the accompanying description above. Although any
methods and materials similar or equivalent to those described
herein can be used in the practice or testing of the present
invention, the preferred methods and materials are now described.
Other features, objects, and advantages of the invention will be
apparent from the description and from the claims. In the
specification and the appended claims, the singular forms include
plural referents unless the context clearly dictates otherwise.
Unless defined otherwise, all technical and scientific terms used
herein have the same meaning as commonly understood by one of
ordinary skill in the art to which this invention belongs. All
patents and publications cited in this specification are
incorporated by reference.
[0033] The foregoing description has been presented only for the
purposes of illustration and is not intended to limit the invention
to the precise form disclosed, but by the claims appended
hereto.
* * * * *